Hyperthermia a Treatment for Cancer: Maturation of its Clinical Application Invited article

Polish J. of Environ. Stud. Vol. 15 No. 4A (2006), 11-15
Invited article
Hyperthermia a Treatment for Cancer:
Maturation of its Clinical Application
G. C. van Rhoon, J. van der Zee
Erasmus MC, Department of Radiation Oncology, Hyperthermia unit, Rotterdam, The Netherlands
Abstract
Hyperthermia (HT) is considered a valuable anti-cancer treatment modality in many Western countries. For
advanced cervical cancer adding HT to radiotherapy (RT) doubles the 3 years survival rate (27 vs. 51%). For
recurrent breast cancer in earlier irradiated areas the local control rate for RT+HT is doubled compared to RT
alone (39 vs. 79%). The doubling of local control – or survival rate following the addition of HT to
conventional therapies without increased toxicity is, in historical perspective, an extraordinary and unsurpassed
finding. Generally, HT is applied by electromagnetic radiation and requires the use of complex high
technological equipment. A strong relation exists between treatment quality and clinical outcome; hence
controlled delivery of heat is the Achilles heel of the treatment.
Keywords: Hyperthermia, electromagnetic heating, dosimetry, quality assurance, clinical response
Clinical trials demonstrating the potential
of hyperthermia in cancer treatment
(Table 1).
Hyperthermia (40-45 °C for 15-60 min.) is always
implemented as part of a multimodal, oncology strategy, i.e.
in combination with radiotherapy (RT) or chemotherapy
(ChT). Extensive biologic research has shown that
hyperthermia (HT) is one of the most if not the most potent
modifier of RT known today [1]. A recent review [2] on
state of the art HT describes selected phase I or II (n=17)
and phase III trials (n=16) investigating the effect of HT
combined with RT (n=10 trials), ChT (n=15 trials), or both
(n=8 trials) in a total of more than 2200 patients. Table 1
shows the results of all phase III trials conducted by
Western research group. All studies but two show a
statistical significant higher (up to a doubling) tumor
control and/or cure rate for the combined treatment
modality. Additionally all studies report comparable acute
and late toxicity in both treatment arms. The positive results
of the most recent trials explain the renewed enthusiasm in
hyperthermia, which is reflected in the growing number of
institutes interested in the application of hyperthermia [3,4].
Impact of the quality of the hyperthermia
treatment on clinical outcome
The importance of adequate heating in HT is well
illustrated by the two studies, which failed to show a
statistical significant benefit for the HT group. In the trial
published by Emami et al. [8] only one patient out of 86
fulfilled the minimal adequacy criteria for the delivery of the
HT treatment. In the RTOG [12,13] study patients with small
chest wall tumors (d3 cm) in the study arm (i.e. with HT)
responded better in comparison to the control arm, but this
was not the case for patients with large chest wall tumors.
The phase III trials coordinated by Vernon et al. [7] and
Overgaard et al. [9] demonstrated a statistical significant
therapeutic advantage of the addition of HT. However, also
in these studies the authors reported that the benefit of HT
for the larger tumors is less obvious in the case of primary
inoperable breast cancer [7] and for melanoma lesions with a
diameter >4 cm [9]. In accordance with the RTOG studies
these authors report that the poorer outcome for large
tumors may reflect the lower ability to heat them
adequately. Overall the positive phase III trials demonstrate
that HT applied with the current state of the art technology,
12
van Rhoon G. C., van der Zee J.
Table 1. Comparison of the results of radiotherapy (RT) versus radiotherapy plus hyperthermia (RT + HT) in randomized trials from
Western research groups.
Reference
Tumor
Endpoint
Jones et al. [26]
Various superficial
All tumors
Previously irradiated
Complete response rate
109
39
42%
24%
66%
68%
3 years overall survival
358
143
101
114
112
308
184
134
44
24%
22%
22%
27%
15%
41%
34%
28%
41%
0%
30%
39%
27%
30%
28%
13%
51%
31%
59%
35%
48%
83%
53%
32%
52%
25%
Sneed et al. [6]
Vernon et al. [7]
Emami et al. [8]
Overgaard et al. [9]
Valdagni et al. [10,11]
All Pelvic tumors@
Bladder
Rectum
Cervixd
Glioblastoma multiforme@
Breast cancer@
Various
Melanoma@
Head & neck@
Perez et al. [12,13]
Various
Van der Zee et al. [5]
2 years survival
complete response rate
2 years survival
2 years local NED
complete response rate
5 years survival
complete response rate overall
in small tumors (diam. <3 cm)
in large tumors (diam. >3 cm)
N
RT
236
55
181
RT + HT
N= number of patients; NED = no evidence of disease; @ Statistical significant difference.
possesses a great promise to improve clinical outcome for
advance cancers. Nevertheless, there exists a strong need to
further improve the HT technology by developing sitespecific HT systems and more sophisticated methods to
assess the quality of the treatment.
Maturation of hyperthermia technology
Heating tissue for hyperthermia involves complex
technology, physiology and biology. The majority of the
hyperthermia treatments are applied using external devices,
employing energy transfer to the tissue by RF or MW technology and to a lesser extend ultrasound technology [14].
Since the early seventies, research has been directed at
the development of techniques to apply and control hyperthermia. Therapeutic temperatures could be achieved in
deep-seated tumors using the first generation equipment for
deep loco-regional HT, but it appeared to be difficult to fulfill the temperature-time goals. To overcome these problems the second generation of the radiative deep heating
devices, such as the BSD2000 system [15], the four-waveguide system [16], and the coaxial TEM applicator [17]
provided the possibility of SAR-steering by phase and
amplitude control or by re-positioning the patient. The third
generation equipment is characterized by an accurate
control of phase and amplitude steering (e.g. solid state
amplifiers with integrated phase-locked loop systems) and
use of a more complicated applicator design, e.g. the Sigma
Eye with 24 instead of the Sigma 60 with 8 dipole elements.
At present, the BSD2000 with the Sigma-60 or Sigma Eye
applicator is the most common deep HT-system in clinical
use. Clinical experience with the BSD2000 indicates that
indeed higher temperatures for longer periods, i.e., a better
quality of the HT treatment, can be achieved.
Facilitated by the enormous progression in computational power, the last decade has brought significant
advances in Hyperthermia Treatment Planning Systems
(HTPS). The currently most advanced 3-d models, having
dynamic non-uniform grid generation and conformal 3D
FDTD scheme supporting high resolution models at critical
structures, are expected to allow a priori selection of the
optimal energy deposition or temperature distribution.
The introduction of Non Invasive Thermometry (NIT)
by Magnetic Resonance Imaging (MRI) represents the last
major technological improvement. Since the clinical introduction of hybrid hyperthermia systems [18-21] it is
possible to perform on-line NIT during high power RFheating. The important potential benefits of NIT can only be
valued properly if placed against the limitations of the only
other option to assess some form of a quality indicator
of the heat treatment, i.e. through invasive thermometry.
The temperature-meters used for invasive thermometry are
characterized by high accuracy, high temporal and spatial
resolution. However, in order to obtain high quality thermometry the temperature probes must be placed at the critical locations [22-24]. In practice, however, the number
of interstitially (or intra-luminal) placed temperature probes
are limited and reserved to “reachable” locations and thus
invasive thermometry provides in nearly all cases only
accidental temperature information which is at best more or
less representative for the overall temperature distribution.
The results obtained thus far with NIT by MRItechnology are very promising and demonstrate its
feasibility. Although, the temperature distribution is still
characterized by a relatively low accuracy and low temporal
Hyperthermia a Treatment for Cancer...
resolution, a most important progress is achieved as NIT by
MRI provides complete 3-dimensional temperature information. The availability of 3D temperature information is
crucial to optimize the energy distribution in the target
region as well as to reduce the effect of unwanted hot-spots
elsewhere in the body during regional hyperthermia
treatments. The logical next step to refine the application
of HT will be on-line control of the transferred power
deposition pattern in order to re-adjust the heating system to
achieve an improved temperature distribution as illustrated
in figure 1.
Finally, MR monitoring during HT is also a mandatory
tool to derive spatial information on the physiological
(perfusion, flow, oxygenation) processes that are temperature dependent and their change may play a significant
role as prognostic factor for the outcome of the multimodality treatment for cancer [25,26].
New knowledge in prognostic factors
for hyperthermia
Since the 1980s thermal cytotoxicity has been the
foundation for the HT treatment design with a temperature
goal for a T90 of 43 °C during 60-90 minutes for 4-8
sessions. Under pressure of the good clinical results of the
13
phase III trials despite the reported low T90’s (39-41 °C) in
all studies, the appropriateness of this view is now strongly
questioned.
The positive results obtained in many phase III trials at
temperatures too low for significant cytotoxicity, cause
abandoning of the “conventional view”, and boosts
international and multi-disciplinary discussions towards
better understanding of the biological processes involved
in HT at realistic, i.e. clinically achievable temperatures [27]. Current new biology concepts for dosimetry in
HT are considering all effects occurring in the temperature
range of 39 to 44 °C that is commonly achieved during
clinical treatments. The special issue of the Int J
Hyperthermia of December 2005 “Thermal Medicine,
Heat Shock Proteins and Cancer” presents an excellent
overview of the wide range of biologic effects involved in
HT: inhibition of radiation-induced damage repair,
changes in perfusion, re-oxygenation, induction of heat
shock response and immunological stimulation, etc.
Needless to say is that the interactions between the
mechanisms and their temperature-time dependency adds
an additional degree of complexity. Hence, exploitation of
these compelling mechanisms in a treatment strategy and
capturing the effectiveness of the HT treatment in a single
“dose”-parameter will be a particular demanding
challenge.
Fig. 1. Schematic lay-out of the treatment optimization protocol for loco-regional hyperthermia in a hybrid system as proposed by P.
Wust, Charité Medical Center, Berlin.
14
van Rhoon G. C., van der Zee J.
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